Vascular Smooth Muscle

The following sections are included:

• Dedication
• Contents

This book covers core concepts in the structure and function of vascular smooth muscle cells in health and disease. Supplemental reading may be drawn from the extensive number of references listed at the end of each chapter. Vascular smooth muscle cell is the major cell type in blood vessels. Dysfunction of vascular smooth muscle cells is an important cause of vascular diseases — for example, atherosclerosis, hypertension, and circulatory shock. Vascular smooth muscle cells are phenotypically plastic, capable of switching between two major phenotypes — contractile/differentiated phenotype and invasive/ proliferative phenotype — in response to environmental clues. This book is organized in three sections. Section I (chapters 2 to 4) addresses the structure and function of the contractile/differentiated phenotype of vascular smooth muscle cell. Section II (chapters 5 and 6) addresses the developmental basis of vascular smooth muscle cell phenotype and structure and function of podosomes (invasive organelles) in the invasive/ proliferative phenotype of vascular smooth muscle cell. Section III (chapters 7 to 9) addresses the role of vascular smooth muscle cell dysfunction in three vascular diseases — atherosclerosis, hypertension, and circulatory shock.

The study of structure and its relationship to function has been, and will continue to be, significant for advancing our understanding of organismal, systems, organ, tissue, cell and sub-cellular physiology. While novel organismal anatomical observations have become rather rare at the gross level, this is far from true at the molecular level where new data on molecular structures continue to expedite advancement of our understanding of their function. William Harvey (1578–1657) is credited with significant advances in our understanding of cardiovascular function through his “exercises” where he applied quantitative reasoning with cardiac and vascular anatomy to derive physiological significance. In so doing he resolved major questions that had no answers, or perhaps worse, had answers but that were incorrect. He is credited with numerous cardiovascular advancements including both ventricles beating simultaneously (not asynchronously), systole forcing blood through the vascular bed (not by vascular contraction), one way circular flow (veins do not carry blood to the tissue), blood recirculation (it is not made in the liver and consumed by the tissue), and valves preventing backflow of blood in the veins (not necessary when the blood is traveling to the tissues via the veins) to list a few. Significant technological advances since Harvey, especially in the past century, have allowed cellular and subcellular anatomy to continue to add to our understanding of function at these levels. Not least of these advances are a host of new and/or refined crystallization methods and microscopic techniques that allow us to “see” things that were never possible before. Thus while much of what we know about the vascular system in general, and smooth muscle cell structure and function specifically has been known for decades and longer, researchers continue to use old and new knowledge of structure (including protein distribution, localization, and interactions) to facilitate our understanding of function. With this in mind, it is the goal of this chapter to review the major structural organization of the vascular smooth muscle cell (SMC), but also to remind the reader that none of what is in the cell is there in isolation. Everything is connected to something else either physically or through sometimes very complex signaling pathways. This chapter will proceed with a brief overview of the vascular system followed by the major molecules in and around the vascular SMC, and then some observations about where this may lead us with further research.

Vascular smooth muscle motor protein regulation acutely adjusts vascular diameters and determines the stress-strain characteristics of arteries and veins. Net muscle contraction occurs when the tension generated by motor proteins is greater than that generated by blood pressure, and net relaxation occurs when pressure- and radius-dependent wall tension exceeds muscle tension. Numerous stimuli generated locally and distantly acting through multiple cell signaling systems modify the level of motor protein activation. Unlike skeletal muscle that is inactive until “called on” to contract, vascular smooth muscle is always “on” to some degree, even when no apparent stimuli are present. Smooth muscle down the vascular tree, and similar vasculatures across species, display some similarities, but also a significant degree of heterogeneity. The canonical vascular smooth muscle contraction control system involves regulation of 20 kDa myosin light chain phosphorylation by Ca²⁺ calmodulin-dependent myosin light chain kinase, rhoA kinase and protein kinase C. The latter two kinases act, in part, by inhibiting the activity of myosin phosphatase, and thus, by increasing the degree of force for a given increase in Ca²⁺. Several novel kinases also appear to participate in myosin light chain regulation, including Ca²⁺-calmodulin-dependent kinase II, mitogen activated protein kinases, zipper-interacting kinase, integrin-linked kinase, kinase inhibitor of NF-κB 2, and AMP-dependent protein kinase. Regulation of vascular smooth muscle contraction is not limited to modulation of myosin light chain phosphorylation. Non-canonical regulation includes control of actin and myosin polymerization, thin filament regulation, latch bridge formation and regulation of force transmission. Stimuli that increase nitric oxide, cyclic nucleotides and their kinases inhibit the contraction control system. The effect of such complex regulation is to maintain blood pressure at levels necessary for perfusion of essential organs, and to ensure appropriate nutrient supply to, and waste removal from, all cells of the body.

Regulation of arterial diameter by control of vascular smooth muscle contraction plays a key role in regulation of blood flow and thereby the supply of O₂ and nutrients to tissues and organs and removal of CO₂ and waste products. A host of contractile stimuli, including agonists such as angiotensin II, serotonin, norepinephrine and endothelin-1, and increases in intravascular pressure (via the myogenic response), elicit vasoconstriction via an increase in cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) leading to activation of calmodulin-dependent myosin light chain kinase, phosphorylation of the regulatory light chains of myosin II (LC₂₀) and cross-bridge cycling. Many contractile stimuli also elicit Ca²⁺ sensitization of contraction via activation of the RhoA/ Rho-associated kinase (ROCK) pathway leading to phosphorylation of MYPT1 (the myosin targeting subunit of myosin light chain phosphatase), a decrease in phosphatase activity and increased LC₂₀ phosphorylation without a change in [Ca²⁺]_i. A third signaling pathway has more recently been implicated in the regulation of vasoconstriction, which involves stimulus-induced polymerization of a pool of actin localized to the sub-plasmalemmal region of the cell and which involves formation of adhesion complexes that transmit force from the myofilaments to the extracellular matrix via transmembrane integrins. Both ROCK and protein kinase C (PKC) have been implicated in stimulus-evoked actin polymerization, ROCK leading to phosphorylation of cofilin (most likely via activation of LIM kinase) and PKC leading directly to phosphorylation of HSP27. Defects in ROCK and PKC signaling and actin polymerization have been implicated in various cardiovascular pathologies.

Vascular smooth muscle cells (SMCs) comprise the predominant cell type in the walls of blood vessels. In adult organisms, SMCs play a role in vascular homeostasis, and their contractile capability helps to sustain vessel tone, as well as mediate hemodynamics. It is intriguing that certain vascular diseases, such as atherosclerosis and aneurysms, tend to afflict specific regions of the larger blood vessels despite most of the identified risk factors being systemic. Interestingly, there is now compelling evidence that SMCs from different blood vessels and even different regions within the same vessel originate from diverse embryonic lineages. This raises the question of whether the intrinsic differences between SMCs underlying different regions of the vasculature may contribute to disease development…

Unlike skeletal and cardiac muscle cells, mature contractile vascular smooth muscle cells (VSMC) are remarkably plastic, capable of switching to the de-differentiated, synthetic/proliferative phenotype, which is motile and invasive. This is achieved in part by remodeling of the actin cytoskeleton triggered by growth factors in response to vascular injury and inflammation. Switching of VSMC from the contractile to the synthetic phenotype is readily demonstrated by passaging VSMC excised from vascular tissues in culture dishes. Expression of contraction-associated markers such as myosin II heavy chain, SM a-actin, calponin, heavy h-caldesmon and SM22α are significantly down-regulated after 3-4 passages of primary VSMC in culture with concomitantly upregulation of migratory markers such as light isoform of caldesmon, l-caldesmon. (Reviewed in)…

Atherosclerosis, an inflammatory disease of arteries, is a leading cause of death worldwide. Atherosclerosis is characterized by the formation of lipid-laden plaque in the vessel wall, causing narrowing of the vessel lumen and reduction in blood flow. In advanced stages of atherosclerosis, the rupture of atherosclerotic plaque can cause the catastrophic event of luminal thrombosis, complete vascular occlusion, cessation of blood flow, and organ damage. The three layers of arterial wall — intima, media, and adventitia — play different roles in the development of atherosclerosis. Intima is the inner layer between endothelium and internal elastic lamina; media is the middle layer between internal elastic lamina and external elastic lamina; adventitia is the outer layer. Vascular smooth muscle cells are present in both intima and media. The importance of vascular smooth muscle cells in the development of atherosclerosis is indicated by the observation that vascular smooth muscle-rich regions of coronary arteries are more prone to the development of atherosclerosis, whereas vascular smooth muscle-sparse regions are more resistant to the development of atherosclerosis. Recent findings suggest that vascular smooth muscle cells play a central role in both the development of atherosclerosis and plaque rupture. During the early stage of atherosclerosis development, vascular smooth muscle cells play a detrimental role in promoting plaque formation. Invasion of medial vascular smooth muscle cells from media to intima and proliferation of vascular smooth muscle cells in the intima together contribute to plaque formation. During the advanced stage of atherosclerosis, vascular smooth muscle cells play a beneficial role in plaque stabilization. Specifically, vascular smooth muscle cells at the fibrous cap of fibroatheroma provide mechanical stability to the structure. Apoptosis of vascular smooth muscle cells at the fibrous cap of atheroma is a major cause of plaque rupture, luminal thrombosis and fatal acute coronary syndrome…

Over the last decade, the cellular impact of non-coding RNAs, defined as RNA molecules not translated into protein, have emerged as an area of great interest. Once thought to only regulate generic functions of cells, namely transcription, translation and splicing, several diverse functions of non-coding RNAs, such as described below for microRNAs and long non-coding RNAs, are now well established.

Vascular smooth muscle cells (VSMCs), the important functional cell in blood vessels, play important roles in vaso dilation and vaso consctriction functions. Circulatory shock-induced ischemia and hypoxia, and internal environment disorder can damage the structure and function of VSMCs, and result in the disorder of vascular contraction and relaxation, which presents as low reactivity to vasoconstrictors and vasodilators is called vascular hypo-reactivity. This reduced vascular reactivity severely interferes with the treatment of circulatory shock, especially interferes with the efficacy of vasoactive agents. Consequently, it is very important to elucidate the mechanisms and search for the effective treatments for VSMC damage and vascular hypo-reactivity. In recent years, many studies focused on the factors inducing VSMC damage, the different features and mechanisms for vascular hyporeactivity, and the treatment approaches following shock. VSMCs are an important target for the treatment of circulatory shock…

The following sections are included:

• Index